Veterinary Antimicrobial Use Regulations An Environment of Change Brian Lubbers, DVM, PhD, DACVCP Director of Clinical Microbiology

Changing Regulations Cephalosporin Extralabel Use Restriction FDA Guidance 209 FDA Guidance 213 Veterinary Feed Directive

Why? Increasing antimicrobial resistance Antimicrobial Exposure Agricultural Use Human Use 80% 20%

Cephalosporin Extralabel Use Restriction Any use that is not on the label Different animal species Different disease Different dose Different route Different frequency or duration of administration Any extralabel use of any drug requires the supervision of a veterinarian

Cephalosporin Extralabel Use Restriction April 2012 FDA issued prohibition of extralabel uses of cephalosporins Cattle, swine, chickens, turkeys For disease prevention Excede® label indication is NOT RESTRICTED At unapproved doses, frequencies, duration or routes of administration For species / production classes not indicated on the label Exceptions: Approved cephapirin products Treatment / Control of an extralabel indication when label dose regimen is used Use in minor species

What was the evidence? Violative residue investigations Poor / nonexistant animal treatment records Inadequate animal ID Lack of animal owner knowledge regarding withdrawal times Drug product administered by extralabel route Drug product administered at extralabel [increased] dose Drug product administered to animal class not approved (veal)

What was the evidence? FDA hatchery inspections Biobullets Ceftiofur use in unapproved doses / methods of administration Biobullets FDA farm / veterinary hospital inspection Use of human-approved cephalosporins (cephalexin) in cattle Increasing cephalosporin resistance in Salmonella - NARMS

How does this impact veterinarians / producers? Minimal direct impacts Increased familiarity with product labels Indirect impacts ENORMOUS “However, the Agency [FDA] believes that it is not limited to making risk determinations based solely on documented scientific information, but may use other suitable information as appropriate.”

How does this impact antimicrobial use? Likely minimal Extralabel use only part of the violative residue issue Production system / Management / Training bigger issues Cephalosporins not widely used in veterinary medicine SALES DATA (kg) Veterinary (2012) Cephalosporins 27,654 Human (2011) % Used in Veterinary 496,910 5%

FDA Guidance 209 The Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals Dec 2013

What was the evidence? Recent Peer-Reviewed Scientific Literature Governmental / Professional Reports

What was the evidence? Recent Peer-Reviewed Scientific Literature Alali (2008) Longitudinal study of antimicrobial resistance among E. coli isolates from integrated multisite cohorts of humans and swine. Sharma (2008) Diversity and distribution of commensal fecal E. coli bacteria in beef cattle administered selected subtherapeutic antimicrobials in a feedlot setting. Alexander (2008) Effect of subtherapeutic administration of antibiotics on the prevalence of antibiotic-resistant E. coli bacteria in feedlot cattle. Harvey (2009) A metagenomic approach for determining prevalence of tetracycline resistance genes in the fecal flora of conventionally raised feedlot steers and feedlot steers raised without antimicrobials. Vieira (2009) Association between tetracycline consumption and tetracycline resistance in E. coli from healthy Danish slaughter pigs. Varga (2009) Associations between reported on-farm antimicrobial use practices and observed antimicrobial resistance in generic fecal E. coli isolated from Alberta finishing swine farms. Alexander (2010) Farm-to-fork characterization of E. coli associated with feedlot cattle with a known history of antimicrobial use. Sapkota (2011) Lower prevalence of antibiotic-resistant Enterococci on US conventional poultry farms that transitioned to organic practices. Vieira (2011) Association between antimicrobial resistance in E. coli isolates from food animals and blood stream isolates from humans in Europe: an ecological study. Mirzaagha (2011) Distribution and characterization of ampicillin- and tetracycline-resistant E coli from feedlot cattle fed subtherapeutic antimicrobials. Looft (2012) In-feed antibiotic effects on the swine intestinal microbiome.

What was the evidence? Governmental / Professional Reports 1969 Report of the Joint Committee on the Use of Antibiotics in Animal Husbandry and Veterinary Medicine “Swann Report” 1970 FDA Task Force Report “The Use of Antibiotics in Animal Feed” 1980 NAS Report “The Effects on Human Health of Subtherapeutic Use of Antimicrobial Drugs in Animal Feeds” 1984 Seattle-King County Study: “Surveillance of the Flow of Salmonella and Campylobacter in a Community” 1988 Institute of Medicine Report: “Human Health Risks with the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed” 1997 WHO Report, “The Medical Impact of Antimicrobial Use in Food Animals” 1999 NRC Report: “The Use of Drugs in Food Animals – Benefits and Risks” 1999 US GAO Report – “Food Safety: The Agricultural Use of Antibiotics and Its Implications for Human Health” 1999 European Commission Report, “Opinion of the Scientific Steering Committee on Antimicrobial Resistance” 2000 WHO Expert Consultation: “WHO Global Principles for the Containment of Antimicrobial Resistance in Animals Intended for Food” 2003 Report “Joint FAO/OIE/WHO Expert Workshop on Non-Human Antimicrobial Usage and Antimicrobial Resistance: Scientific assessment” 2003 IOM Report, “Microbial Threats to Health: Emergence, Detection and Response” 2004 Report, “Second Joint FAO/OIE/WHO Expert Workshop on Non-Human Antimicrobial Usage and Antimicrobial Resistance: Management Options” 2004 US GAO Report – “Antibiotic Resistance: Federal Agencies Need to Better Focus Efforts to Address Risks to Humans from Antibiotic Use in Animals” 2005 Codex, “Code of Practice to Minimize and Contain Antimicrobial Resistance” 2006 Antimicrobial Resistance: Implications for the Food System, Comprehensive Reviews in Food Science and Food Safety 2009 American Academy of Microbiology. Antibiotic Resistance: An Ecological Perspective on an Old Problem 2011 WHO Report: Tackling antibiotic resistance from a food safety perspective in Europe

Literature and Report Summary Use of antimicrobials is associated with the development of resistant bacteria Pathogens (and their resistance elements) move from animals to people through the food chain Quantitative risk assessments are needed to determine level of risk ?

Image from: Health Canada

In the absence of quantitative risk…… Increasing antimicrobial resistance Antimicrobial Exposure Agricultural Use Human Use 80% 20%

Literature and Report Summary (continued) Increased surveillance for: Resistant bacteria Antimicrobial consumption Develop strategies to limit the need for antimicrobials (husbandry) New modalities for prevention and treatment should be researched Eliminate the use of medically important antimicrobials as growth promoters Increase veterinary oversight of antimicrobial use

How does this impact veterinarians / producers? The Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals Principle 1: The use of medically important antimicrobial drugs in food-producing animals should be limited to those uses that are considered necessary for assuring animal health. FDA Guidance 213 Principle 2: The use of medially important antimicrobial drugs in food-producing animals should be limited to those uses that include veterinary oversight or consultation. Veterinary Feed Directive

FDA Guidance 213 New Animal Drugs and New Animal Drug Combination Products Administered in or on Medicated Feed or Drinking Water of Food-Producing Animals: Recommendations for Drug Sponsors for Voluntarily Aligning Product Use Conditions with GFI 209 Dec 2013 Provides Animal Health Companies with Direction for Removing Non-Therapy Label Indications

FDA Guidance 213 Applies to: Medically important antimicrobials Used in or on medicated feed or water of food producing animals For production purposes

Medically important antimicrobials… Does not include Ionophores – monensin (Rumensin ®), lasalocid (Bovatec ®) Bacitracin Bambermycins – Flavomycin® Pleuromutilins – tiamulin (Denagard®) Not listed in FDA 152, but is on the WHO medically important list

Medically important antimicrobials with food animal indications Aminoglycosides Neomix® 325 Lincosamides LS 50 Macrolides Tylan 100® Penicillins Florfenicol Nuflor ® Streptogramins Sulfonamides Tetracyclines Aureomycin® Veterinary (2012) Percent Total Veterinary Use Aminoglycosides 273,536 2% Lincosamides 218,140 Macrolides 616,274 4% Penicillins 965,196 7% Sulfas 493,514 3% Tetracyclines 5,954,361 41% NIR / Other 1,495,959 10%

For Production Purposes Treatment / Prevention / Control labels NOT affected “increased rate of weight gain” “improved feed efficiency” Aureomycin® Control of active infection of anaplasmosis caused by Anaplasma marginale susceptible to chlortetracycline Increased weight gain

Where are we with Guidance 213? December 2013 3 month period for drug sponsors to indicate compliance 26 drug sponsors 283 drug products affected July 1 2014 All sponsors committed to comply 31 labels withdrawn 2 label changes approved 1 added requirement for veterinary oversight 1 production indication dropped 3 year window for full implementation

How does this impact veterinarians / producers? Minimal Guidance 213 impacts drug sponsors Many of the withdrawn labels were for products that were not actively being marketed

How does this impact antimicrobial use? 16% 2% 32% 1.5% 16% 160,270 15% 1,068,964 Apley (2012) Foodborne Pathogens and Disease

How does this impact antimicrobial use? Apley (2012) Foodborne Pathogens and Disease

Veterinary Feed Directive FDA Guidance 120 Questions and Answers concerning VFDs

Where are we with VFDs? Final revisions not yet available Addressing concerns with original VFD language / logistics Limited experience with VFD process Only 3 products currently under VFD regulations [1 is not currently marketed] Administrative burdens Proposed record keeping reduction from 2 years to 1 year Veterinary workforce limitations Revised VCPR language VCPR requirements now fall to the states Impacts on feed industry Eliminate reclassification of VFD drugs to Category II

How will this impact veterinarians / producers? Huge Impacts Veterinarians & producers will now be responsible and accountable for antimicrobial use in food animals Documentation is going to extend well beyond VFD Treatment protocols Treatment records Training records

How will this impact antimicrobial use? Minimal Isn’t intended to reduce appropriate use

QUESTIONS?